We sought to define the impact of echocardiographically defined left ventricular (LV) lead position on the efficacy of cardiac resynchronization therapy (CRT) in a serial study using 3-dimensional echocardiography. Fifty-eight consecutive patients (53+/-9 years of age; 37 men) with heart failure were included in the study. Echocardiograms were obtained before CRT, within 7 days after implantation, and at 12+/-2 months of follow-up using a 3-dimensional digital ultrasound scanner (iE33, Philips, Andover, Massachusetts). Analysis of the temporal course of contraction in 16 LV segments was performed offline using a semiautomatic contour tracing software (LV Analysis, TomTec, Unterschleissheim, Germany). Based on the resulting volume/time curves the segment with the latest minimum of systolic volume in each patient was identified preoperatively (segment A). In addition, the temporal difference between the pre- and postoperative (within 7 days) minimum of systolic volume was determined for each segment. The segment with the longest temporal difference was defined to show the greatest effect of CRT. Location of the LV lead tip was assumed to be within this segment (segment B). LV lead position was defined as optimal when segments A and B were equal and as nonoptimal when they were far from each other. Using this definition, 26 patients had a nonoptimal and 32 patients an optimal LV lead position. Before CRT ejection fraction (32+/-4% vs 31+/-6%), LV end-systolic and end-diastolic volumes (242+/-92 vs 246+/-88 ml, 315+/-82 vs 323+/-90 ml), and peak oxygen consumption (14.3+/-1.4 vs 14.6+/-1.5 ml/min/kg) were equal in the 2 groups. At 12+/-2 months of follow-up, patients with an assumed optimal LV lead position showed greater increases of ejection fraction (10+/-2% vs 6+/-3%) and peak oxygen consumption (2.4+/-0.3 vs 1.5+/-0.4 ml/min/kg) and greater decreases of LV end-systolic (32+/-7 vs 21+/-5 ml) and end-diastolic (20+/-7 vs 13+/-6 ml) volumes. In conclusion, correspondence of the segment with the latest preoperative LV contraction with the segment with the greatest effect based on CRT results in a significantly greater benefit of ejection fraction and peak oxygen consumption and a greater improvement in LV remodeling. Thus, there is an optimal LV lead position that should be obtained.